Process for the preparation of 1-(aminomethyl) cyclohexaneacetic acid

ABSTRACT

A conversion process of gabapentin hydrochloride into gabapentin comprising: a) dissolution of gabapentin hydrochloride in a solvent in which the gabapentin hydrochloride and the gabapentin are completely soluble; and b) subsequent addition of an amine that allows the removal of the chloride ion from the solution containing gabapentin hydrochloride, by precipitation of the hydrochloride of the same amine, leaving the gabapentin in solution in free amino acid form.

FIELD OF THE INVENTION

The present invention concerns a preparation process of 1-(aminomethyl)cyclohexaneacetic acid (GABAPENTIN).

PRIOR ART

GABAPENTIN, characterized by the following structural formula (I)

is an active principle mainly used in human therapy for the treatment ofcerebral disease, namely epilepsy (“Drugs of the future”, vol. 9, N^(o)6, 1984, pp. 418- 419). Various processes are described in the art forthe synthesis of this molecule. The American patent U.S. Pat. No.4,024,175 describes the preparation of GABAPENTIN starting from itshydrochloride salt, by treatment of an aqueous solution of the latterwith ion exchange resins, so as to remove the chloride ion and make theGABAPENTIN molecule available in a free amino acid form. The solutionobtained at the end of the treatment is concentrated by distillation andthe residue is recovered with alcohols to allow the isolation ofGABAPENTIN. However, this process is complex and difficult, particularlydue to the specific plant engineering technology necessary to remove thechloride ion and make GABAPENTIN available in a free amino acid form.

The WO patent 98/28255 contains a description for the preparation ofGABAPENTIN starting with its hydrochloride salt, in which elimination ofthe chloride ion is achieved in a different way from that described inthe previous patent. After having solubilized GABAPENTIN HYDROCHLORIDEin suitable non-aqueous solvents, an amine is added to the resultantsolution which salifies the chloride ion, making it soluble, and thusallowing the precipitation of GABAPENTIN in a new polymorphic formcalled “FORM III”, which differs from the polymorphic form known as“FORM II”, which is that most widely used and sold. The GABAPENTINobtained in the polymorphic form known as “FORM III”, is necessarilytransformed into the polymorphic form “FORM II” by treatment withalcohols. In addition, this treatment has the disadvantage of not beingable to recover the used amine and recycle it in the salification stageof the chloride ion. Therefore the need was felt for a preparationprocess of GABAPENTIN in the polymorphic form “FORM II”, that ofgreatest use and commercial diffusion, starting with GABAPENTINHYDROCHLORIDE, able to overcome the technical drawbacks connected withthe need to use facilities for ion exchange resins, and able to avoidpassing through a polymorphic form “FORM III” of GABAPENTIN, differentfrom the one on the market.

SUMMARY

A new separation process of GABAPENTIN in the polymorphic form “FORMII”, has now been found, starting with GABAPENTIN HYDROCHLORIDE, capableof overcoming technical drawbacks and those connected with the need topass through an unusable crystalline form on sale, typical of theprocesses known in the art.

The applicant has unexpectedly and surprisingly found a new separationprocess of GABAPENTIN in the polymorphic form “FORM II”, starting withGABAPENTIN HYDROCHLORIDE, in which the chloride ion is eliminated byprecipitating it as an insoluble salt, releasing GABAPENTIN in solutionin free amino acid form.

DETAILED DESCRIPTION OF THE INVENTION

A conversion process of gabapentin hydrochloride into gabapentintherefore constitutes a purpose of the present invention comprising:

a) dissolution of gabapentin hydrochloride in a solvent in which thegabapentin hydrochloride and the gabapentin are completely soluble; and

b) subsequent addition of an amine that allows the removal of thechloride ion from the solution containing gabapentin hydrochloride, byprecipitation of the hydrochloride of the same amine, releasinggabapentin in solution in free amino acid form.

The solvent used at stage a) to completely solubilize gabapentinhydrochloride is preferably an aqueous solvent, more preferably asolvent consisting of at least 50% by weight of water, more preferablythe solvent consists of at least 70% by weight of water, more preferablythe solvent consists of at least 90% by weight of water, still morepreferably the solvent is water.

The amine used at stage b) to remove the chloride ion is preferably anamine with cycloalkyl or aryl substituents, more preferably it isselected from the group consisting of monocyclohexylamine,dicyclohexylamine, dibenzylamine, tricyclohexylamine, or their mixtures,still more preferably it is dicyclohexylamine.

The dissolution at stage a) is carried out at a temperature whichdepends on the solvent used and such as to allow the completedissolution of gabapentin hydrochloride and gabapentin, the temperatureis preferably between 10° and 90° C., more preferably between 20° and70° C., still more preferably between 30° and 50° C.

One of the particularly preferred embodiments of the conversion processof gabapentin hydrochloride into gabapentin, according to the presentinvention, comprises, in addition to stages a) and b) as above, theremoval stage. c) by filtering the precipitate of the aminehydrochloride, from the solution containing gabapentin in free aminoacid form, and the recovery of the amine by the alkali treatment of theamine hydrochloride to give the free amine which is recycled at stageb).

An additional preferred embodiment of the process, according to thepresent invention comprises, in addition to stages a), b) and c), asabove, also stage d) wherein the solution containing gabapentin in freeamino acid form is concentrated by distillation and the residue isrecovered with alcohols selected from the group consisting of alkylalcohols with one to four linear or branched carbon atoms, or theirmixtures, preferably ethyl alcohol, to give the isolation of gabapentinin polymorphic form “FORM II”.

An additional preferred embodiment of the present invention comprises,in addition to the stages a), b), c) and d), also stage e) whereingabapentin in polymorphic form “FORM II”, isolated at stage d), ispurified by treatment with alcohol selected from the group consisting ofalkyl alcohols with one to four linear or branched carbon atoms, ortheir mixtures, preferably a methyl alcohol/isopropyl alcohol mixture.

More particularly, according to the present invention, formula (II)gabapentin hydrochloride is used as a process intermediate

prepared due to the well known “Hoffmann rearrangement” reaction; thisreaction consists in making the formula (Ill) compound react

with sodium or potassium hypochlorite, or sodium or potassiumhypobromite to give an intermediate isocyanate that, because of thesubsequent rearrangement, leads to the formation of gabapentin, isolatedas a hydrochloride by acidification of the reaction environment withhydrochloric acid. The intermediate of formula (II) gabapentinhydrochloride is completely solubilized in aqueous solvent, in this casewater, and an amine is added to the solution obtained, in this case,dicyclohexylamineof formula (IV)

able to move the chloride ion from gabapentin, it being salified; thedicyclohexylamine hydrochloride of formula (V) thus formed

is insoluble in aqueous environment, while gabapentin, thus renderedavailable in free amino acid form, vice versa proves soluble in thisenvironment.

The suspension obtained is filtered recovering, on the one hand, anaqueous solution containing gabapentin in a free amino acid form and, onthe other, a solid (cake) of amine hydrochloride, in this case,dicyclohexylamine hydrochloride, which treated with strong bases,preferably hydroxides of alkaline metals, more preferably sodiumhydroxide, thus allows the recovery of the amine, in this case, thedicyclohexylamine, and its recycling. The aqueous solution containinggabapentin is concentrated by distillation until the start ofprecipitation, with the residue taken back with an alkyl alcohol, inthis case ethanol. The suspension obtained is filtered, resulting ingabapentin in the polymorphic form “FORM II”, with content of impurityof formula (VI)

of less than 0.05% by weight.

The process, subject of the present invention, also has the advantagethat any presence of gabapentin hydrochloride or amine, in this casedicyclohexylamine, in the aqueous solution obtained after the removal ofamine hydrochloride, in this case dicyclohexylamine hydrochloride, isabsent in the alcoholic mother waters from which gabapentin is isolatedin the polymorphic form “FORM II”.

The raw gabapentin obtained is treated under reflux with alcoholselected from the group consisting of alkyl alcohols with one to fourcarbon atoms, linear or branched, or their mixtures, preferably a methylalcohol/isopropyl alcohol mixture, and the suspension thus obtained isbrought to 0° C. and filtered, obtaining gabapentin with polymorphicform “FORM II”, verified by FTIR and X-Ray analyses, and having a HPLCpurity in excess of 99.9%.

Below are some illustrative, but non-limiting examples of the presentinvention.

EXAMPLE 1

100 g of gabapentin hydrochloride are solubilized in 500 g of deionizedwater and 90 g of dicyclohexylamine are added while heating to 30°-50°C. An abundant precipitation of dicyclohexylamine hydrochloride isproduced that is filtered with a Buchner funnel. The dicyclohexylaminehydrochloride solid is treated with sodium hydroxide, thus regaining thedicyclohexylamine that is thus recovered and recycled in the separationstage of the chloride ion by precipitation, while the aqueous solutioncontains gabapentin in free amino acid form.

The aqueous solution obtained by filtering is distilled under reducedpressure, until the start of precipitation, and the residue is takenback with ethyl alcohol, heated to 40°-50° C., and the suspensionobtained is cooled for a few hours and filtered.

The solid obtained is vacuum dried at 30°-40° C., producing rawgabapentin in the polymorphic form “FORM II” with a formula (VI)impurity content of less than 0.05%. The yield is 80%.

EXAMPLE 2

50 g of raw gabapentin arising from example 1 are suspended in 250 g ofmethyl alcohol and 125 g of isopropyl alcohol. It is heated under refluxfor 30 minutes, and cooled at 20-25° C. for two hours and subsequentlyat 0° C. for a further two hours. The suspension is filtered with aBuchner funnel and is vacuum dried at 30°-40° C., producing gabapentinof polymorphic form “FORM II” with a HPLC purity greater than 99.85%.

1. A conversion process of gabapentin hydrochloride into gabapentincomprising: a) dissolution of gabapentin hydrochloride in a solvent inwhich the gabapentin hydrochloride and the gabapentin are completelysoluble; and b) subsequent addition of an amine that allows the removalof the chloride ion from the solution containing gabapentinhydrochloride, by precipitation of the hydrochloride of the same amine,leaving gabapentin in solution in free amino acid form.
 2. A processaccording to claim 1 wherein the solvent used at stage a) is an aqueoussolvent.
 3. A process according to claim 2 wherein the solvent is asolvent consisting of at least 50% by weight of water.
 4. A processaccording to claim 2 wherein the solvent consists of at least 70% byweight of water.
 5. A process according to claim 2 wherein the solventconsists of at least 90% by weight of water.
 6. A process according toclaim 2 wherein the solvent is water.
 7. A process according to claim 1wherein the amine used at stage b) is an amine with cycloalkyl or arylsubstituents.
 8. A process according to claim 7 wherein the amine isselected from the group consisting of monocyclohexylamine,dicyclohexylamine, dibenzylamine, tricyclohexylamine, or their mixtures.9. A process according to claim 8 wherein the amine isdicyclohexylamine.
 10. A process according to claim 1 further comprisingthe removal stage c) the removal by filtering of the precipitate of theamine hydrochloride, from the solution containing gabapentin in freeamino acid form.
 11. A process according to claim 10 wherein thehydrochloride of the amine is treated with alkalis in order to obtainthe free amine which is recycled at stage b).
 12. A process according toclaim 10 further comprising stage d) wherein the solution containinggabapentin in free amino acid form is concentrated by distillation andthe residue is taken back with alcohol selected from the groupconsisting of alkyl alcohols with one to four carbon atoms, linear orbranched, or their mixtures, to give the isolation of gabapentin inpolymorphic form “FORM II”.
 13. A process according to claim 12 whereinthe alcohol is ethyl alcohol.
 14. A process according to claim 12further comprising stage e) wherein gabapentin in polymorphic form “FORMII”, isolated at stage d), is further purified by treatment with alcoholselected from the group consisting of alkyl alcohols with one to fourcarbon atoms, linear or branched, or their mixtures.
 15. A processaccording to claim 14 wherein the alcohol is a methyl alcohol/isopropylalcohol mixture.